Phosphate Binder No Help for Heart in CKD

Action Points

Note that this single-center, randomized controlled trial failed to demonstrate an effect of sevelamer on left ventrical hypertrophy in patients with stage 3 chronic kidney disease.

Be aware that for most of these patients, serum phosphate levels were in the normal range prior to starting the trial.

Patients with chronic kidney disease saw no improvement in cardiovascular outcomes when treated with the phosphate-binding agent sevelamer, results of a randomized trial showed.

After 40 weeks of treatment, investigators saw no improvement in left ventricular (LV) mass, LV function, or arterial stiffness in patients who received sevelamer, when compared with those on placebo.

The drug was not well tolerated, but in a relatively small group of adherent patients, treatment with sevelamer was associated with lower urinary phosphate and serum fibroblast growth factor-23 (FGF-23). However, serum phosphate, klotho, vitamin D, and cardiovascular outcomes did not improve, as reported online in the Journal of the American Society of Nephrology.

"In patients with stage 3 chronic kidney disease, the use of sevelamer carbonate for 40 weeks was not associated with any significant changes in LV mass, arterial stiffness, or any parameters of LV systolic and diastolic function," Charles J. Ferro, MD, of the University of Birmingham in England, and co-authors concluded.

"However, adherence to the study medication was low, and more rigorous testing of this hypothesis may be achieved with the introduction of a well-tolerated, one-time-daily regimen that more effectively reduces cardiovascular phosphate exposure."

Serum phosphate has emerged as a predictor of cardiovascular risk. Chronic kidney disease (CKD) is the most common cause of impaired phosphate handling, and the initial studies establishing the link between phosphate and cardiovascular outcomes involved dialysis patients, according to the authors.

CKD patients' increased cardiovascular risk cannot be fully explained by atherosclerosis, directing attention toward factors such as arterial stiffness and structural heart disease, the authors continued. LV mass has a graded relationship with serum phosphate, and more than 70% of dialysis patients have LV hypertrophy (LVH).

"An understanding of the early pathophysiology of increased LV mass and LVH is essential for designing novel therapeutic strategies to attenuate cardiovascular disease in CKD," the authors stated.

Investigators hypothesized that reducing phosphate absorption with sevelamer would reduce FGF-23 and other phosphatonins, leading to reductions in LV mass and arterial stiffness and improvement in LV systolic and diastolic function.

To test the hypothesis, 120 patients with nondiabetic stage 3 CKD were recruited into a randomized, placebo-controlled evaluation of sevelamer. All patients received a 4-week, open-label sevelamer run-in, followed by randomization to an additional 36 weeks of sevelamer or placebo. The primary endpoint was change in LV mass.

LV mass and function were assessed by cardiac MRI and echocardiography, and arterial stiffness by carotid-femoral pulse wave velocity.

The 109 patients who entered randomized therapy had a mean age of 55 and mean estimated glomerular filtration rate of 50 mL/min/1.73 m2.

At baseline both groups had normal-range values for serum phosphate, serum calcium, parathyroid hormone, klotho, and 1,25-hydroxyvitamin D. Serum FGF-23 and urinary phosphate were elevated. Both groups had well-controlled blood pressure, and about half of the patients had aortic calcification. LV mass, function, and volumes all were in the normal range.

Overall, 97 patients completed the 40 weeks of evaluation, and 104 patients were included in the intention-to-treat analysis.

When the study ended, the sevelamer and placebo groups did not differ significantly with respect to any of the biochemical parameters assessed. LV mass and all indices of LV function also did not differ between groups.

The author of a related editorial did not find the results particularly surprising, as the study "adds to the growing list of null trials in nephrology."

"Individuals with CKD who are likely to benefit from sevelamer or a phosphate binder are those who have hyperphosphatemia or secondary hyperparathyroidism," wrote Rajiv Agarwal, MD, of Indiana University in Indianapolis. "This study does not answer the question of whether treatment of hyperphosphatemia benefits the cardiovascular system. In other words, it did not ask the question of whether reducing the serum phosphorus concentrations among individuals with hyperphosphatemia reduces left ventricular hypertrophy.

"Had the investigators studied people with progressive CKD who had both hyperphosphatemia and increased left ventricular mass, randomized them to either drug or placebo, and diligently reduced serum phosphorus concentration, an improvement in left ventricular mass and function may have been evident in 9 months."